Abstract: Subproject 3 FM. Fibromyalgia is a prevalent and poorly-treated pain syndrome mediated by unknown mechanisms. The clinical features of fibromyalgia include widespread spontaneous pain and increased sensifivity to pain evoked by blunt pressure Accumulating evidence that includes disfinct subgroups suggests that fibromyalgia is mediated by multiple mechanisms. The common presence of comorbitifies such as disturbed sleep, fatigue, stiffness, and dyscognition in fibromyalgia and the overiap with other disorders such as episodic migraine, temporomandibular disorders, irritable bowel syndrome and vulvar vestibulitus syndrome suggest that these multiple mechanisms are not specific to a single disorder. One such mechanism is altered descending pain inhibifion. In healthy individuals, noxious stimulation applied anywhere on the body evokes generalized widespread analgesia referred to as Diffuse Noxious Inhibitory Controls (DNIC). Several studies have failed to demonstrate DNIC in patients with fibromyalgia, supporting the parsimonious concept that the widespread pain symptoms in fibromyalgia may result from a defect in this intrinsic widespread analgesic system. Establishing the precise role of DNIC and related regulatory mechanisms in fibromyalgia will greatly advance the scant knowledge about the underiying mechanisms of this disorder and lead to more efficacious, meiDhanistic-based treatments. The proposed work will extensively characterize a large group of fibromyalgia pafients using phenotyping and genotyping methods that will also be applied to related disorders such as vulvar vestibulitus syndrome and episodic migraine. The central hypothesis for the proposed research is that fibromyalgia represents the combined effects of mulfiple mechanisms that interfere with tonic pain inhibition, resulfing in the spontaneous and evoked pain symptomatology observed with fibromyalgia. This hypothesis will be investigated by additional methods that examine causal relationships between the function of pain inhibitory systems and the magnitude of clinical pain, and that use functional neuroimaging to evaluate the role of pain inhibitory mechanisms. Identifying multiple common mechanisms will provide targets for future therapeutic interventions.